NanoBridge System Enables Targeted Modification of Hard-to-Drug Proteins in Living Cells
Researchers have developed a modular system called NanoBridge that can edit post-translational modifications (PTMs) on proteins that previously lacked accessible small-molecule binding sites. The platform uses biological binders to redirect a small protein tag to target proteins, then employs heterobifunctional small molecules to recruit endogenous modification enzymes. This expands the toolkit for studying disordered or 'undruggable' proteins implicated in cancer and other diseases.
Scientists report the development of NanoBridge, a generalizable platform for editing post-translational modifications (PTMs) on endogenous proteins inside living cells, including those that are largely unstructured and lack well-defined small-molecule binding pockets. The system works by using biologic binders to transiently direct a small protein tag, FKBP12(F36V), to unmodified target proteins, after which heterobifunctional small molecules recruit endogenous PTM enzymes to carry out the desired modification. The approach was validated against three structurally diverse and largely disordered proteins: BCL11A, a hemoglobin regulator; KRAS, a well-known cancer driver; and p53, a major tumor suppressor. Using eight distinct protein binders across these targets, the NanoBridge successfully mediated targeted degradation, phosphorylation, and acetylation in a rapid, reversible, and temporally controlled fashion. Compared to existing chemically induced proximity (CIP) methods, NanoBridge offers greater flexibility to induce multiple PTM types on the same protein of interest without introducing exogenous PTM-writing enzymes, potentially opening new avenues for both basic research and therapeutic development.
What's missing
The study is a preprint posted to bioRxiv and has not yet undergone peer review. Key limitations not fully addressed include whether NanoBridge performs comparably in primary cells or in vivo models versus the cell-line systems tested, the potential for off-target effects from the biologic binders or heterobifunctional small molecules at physiological concentrations, and the scalability and immunogenicity of biologic binders as potential therapeutic agents.
What different sources said
- bioRxivCenter
The NanoBridge system for targeted post-translational modification of challenging proteins
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